The microenvironment in atherosclerosis: molecular regulation mechanism and immunotherapy

• Exploration of the role of immune cells in atherosclerosis and their potential as therapeutic targets. • Discuss the importance of understanding immune cell crosstalk and signaling pathways for developing targeted atherosclerosis therapies. • Analysis of key inflammatory signaling pathways, such as TLRs, NLRP3 inflammasome, and PCSK9, in atherosclerotic inflammation. • Overview of emerging immunotherapies for atherosclerosis, including colchicine, canakinumab, and vaccine development. Atherosclerosis is a chronic inflammatory disease closely linked to immune dysregulation. The immune microenvironment within atherosclerotic lesions is highly complex, involving diverse innate and adaptive immune cells and their intricate crosstalk. These immune interactions collectively contribute to plaque formation, progression, and destabilization. This review comprehensively examines the roles of key immune cell populations—including macrophages, dendritic cells (DCs), neutrophils, mast cells, natural killer (NK) cells, T cells, and B cells—in regulating inflammation, foam cell formation, and lesion stability. Special attention is given to intercellular regulatory circuits such as the Th1–M1 feedback loop, the OX40L–Th17 axis, and DC–T–NK amplification loops. Furthermore, the review highlights the influence of immunometabolic reprogramming on immune cell function and plaque phenotype, illustrating how metabolic states shape inflammatory outcomes. It also discusses the contribution of key signaling pathways—including Toll-like receptors (TLRs), the NOD-like receptor protein 3 (NLRP3) inflammasome, and proprotein convertase subtilisin/kexin type 9 (PCSK9)—to atherosclerotic inflammation and plaque vulnerability. Advances in immunotherapy are also reviewed, including anti-inflammatory agents such as colchicine and canakinumab, as well as emerging vaccine strategies targeting lipid metabolism and vascular inflammation. A deeper understanding of immune cell interplay and signaling dynamics in atherosclerosis will provide a foundation for developing more effective, multi-targeted immunotherapeutic interventions. Future research should aim to refine these strategies to maximize efficacy and safety, with the goal of reducing the global burden of atherosclerotic cardiovascular disease.